Abstract
DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage-induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a "BRCA-like" state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage-inducing agents.
Highlights
DNA damage response plays important roles in cancer development and is a major focus of attention in cancer therapy [1, 2]
Inagar propidium iodide (PI) staining showed that the Icmt−/− cells placed in soft agar underwent massive apoptosis (Figs 1D and S1), whereas under the adherent condition there was no significant elevation in apoptosis for Icmt−/− cells compared to the Icmt+/+ cells (Fig S1)
A role for isoprenylcysteine carboxylmethyltransferase (ICMT) in regulating DNA damage repair has not been previously recognized, despite multiple reports of cell cycle arrest associated with ICMT inhibition [48, 90]
Summary
DNA damage response plays important roles in cancer development and is a major focus of attention in cancer therapy [1, 2]. The resilience and adaptation to DNA damage–induced genomic instability contributes to cancer development [12]; many cancers arise because of an impairment of the DNA damage repair machinery and associated genomic instability [13, 14]. Cancer cells that have intact or elevated DNA repair capacity are significantly more resistant to PARP1-targeting agents [22, 23, 24, 25]. For these cancers, PARP inhibitors have been used in combination with other targeted therapy to increase efficacy [26, 27, 28, 29, 30]. The ever-expanding efforts to understand the multifaceted regulation of DNA damage repair are identifying novel and effective synthetic lethality combinations to increase the responsiveness of cancers, those having efficient DNA repair machinery that are otherwise resistant to DNA damage–inducing approaches such as irradiation or PARP inhibitor [31, 32]
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